Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Abstract

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERα α α α (P = 0.006) and ERβ β β β LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis. (Cancer Sci 2005; 96: 645-652) E ndometrial carcinoma is one of the most common pelvic malignancies among women worldwide, and its incidence has recently increased.(1,2) In situ estrogen metabolism, including synthesis and degradation, has been recently recognized as a very important factor in the development and progression of various human estrogen-dependent neoplasms, including endometrial carcinoma, especially the endometrioid type. (3,4) In endometrial carcinoma, in situ 17β-estradiol (E2) availability has been reported to be closely associated with the pathogenesis and development of endometrial proliferative disorders including endometrial hyperplasia and carcinoma, especially the endometrioid type.(5) DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family.(6,7) DAX-1 is expressed in the adrenal cortex, ovary, Leydig cells and other endocrine cells such as testicular Sertoli cells, pituitary gonadotropes, vent...

Tumorigenic Role of Orphan Nuclear Receptor NR0B1 in Lung Adenocarcinoma

“…In contrast, the knocked-down expression of NR0B1 did not affect the cell proliferation of A549 cells. This might be attributable to the difference of cell types; Saito et al 26 and Nakamura et al 28 did not find any correlation of NR0B1 expression level with the Ki-67 labeling index, a well-established marker for cell proliferative activity, in the endometrial adenocarcinoma of uterus and prostate. The present study on the clinical cases of lung adenocarcinoma showed that NR0B1 expression level did not correlate with the size of tumors.…”

“…26,28 Whereas, the subcellular localization of NR0B1 was various among cases with the present lung adenocarcinoma. Kawajiri et al 43 reported that NR0B1 localization changed during pituitary development from nucleocytoplasmic at embryonic day 10.5 to nucleus at day 18.5.…”

“…Few signals could be detected in several cases ( Figure 9E). According to the method by Saito et al, 26 a total of more than 500 tumor cells from three different representative fields were examined, and the proportion of cells with NR0B1 signals was counted. The previous reports on NR0B1 expression in endometrial adenocarcinoma 26 and prostatic carcinoma 28 used a cut-off point of 10%.…”

“…According to the method by Saito et al, 26 a total of more than 500 tumor cells from three different representative fields were examined, and the proportion of cells with NR0B1 signals was counted. The previous reports on NR0B1 expression in endometrial adenocarcinoma 26 and prostatic carcinoma 28 used a cut-off point of 10%. Therefore, in this study, we used the same cut-off point; the cases with more than 10% positive cells and fewer than 10% positive cells were defined as NR0B1-hi and NR0B1-lo, respectively.…”

Nuclear Receptor DAX1 in Human Prostate Cancer: A Novel Independent Biological Modulator

“…In addition, DAX1 is known to act as a negative regulator of steroid production [10][11][12][13]. DAX1 has also been demonstrated to repress Ad4BP/SF-1-mediated transactivation of other steroidogenic genes, and to act as a corepressor for AR, PR, and ERβ [14][15][16][17][18][19][20]. These interactions could play significant roles by influencing sex-steroid signaling pathways.…”